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Mom’s advice to “take your vitamins” may apply to spinach-shunning youngsters but won’t do much good for boosting brain function in Alzheimer disease patients, at least when it comes to certain B vitamins. That’s the conclusion of an 18-month randomized trial that found no cognitive benefit from high-dose folate, vitamin B6, and vitamin B12 supplementation in seniors with mild to moderate AD. Though discouraging, the results—which appear in this week’s JAMA—do not close the book on vitamin B as a possible intervention for AD and other dementias. Future analyses may identify subgroups of people who could benefit from such regimens, though experts remain cautious about making predictions or recommendations without confirmation from randomized trials. Meanwhile, a survey study supports a potential role for vitamin D deficiency in Parkinson disease.

Folate and vitamins B6 and B12 were chosen for the recent AD trial because they help metabolize homocysteine, a sulfur amino acid that has been shown to mediate neuropathological activity in AD mouse models (Kruman et al., 2000; Kruman et al., 2002). More recent work (Irizarry et al., 2005; Luchsinger et al., 2007) has highlighted a possible connection between levels of homocysteine and plasma amyloid in AD patients, and another study found that two years of daily vitamin B treatment (2 mg folate, 25 mg B6, and 400 μg B12) could reduce plasma Aβ40 levels (Flicker et al., 2006). Furthermore, an eight-year prospective study of 1,092 dementia-free elderly linked high homocysteine levels (>14 micromol/L) with doubled risk of dementia and AD (see Seshadri et al., 2002 and ARF related news story). “All together we really thought this was a very plausible target for intervention,” said Paul Aisen, director of the Alzheimer's Disease Cooperative Study (ADCS) at the University of California, San Diego, and lead investigator on the new study. “It's disappointing that we were not able to change the course of disease.”

Conducted by the ADCS, the study enrolled 409 adults with mild to moderate AD (ages 50 and over, MMSE scores 14-26) at 40 U.S. sites. People with vitamin B or renal insufficiencies were excluded, as were those taking sedatives, Parkinson disease medications, or investigational AD drugs. Stable use of approved AD treatments (cholinesterase inhibitors and memantine) was allowed. Forty percent of eligible subjects were randomized to placebo pills, 60 percent to active treatment (5 mg folate, 25 mg B6, and 1 mg B12 daily). The study drug had more than 10 times the amount of folate in a typical multivitamin. Nevertheless, the investigators restricted enrollment of multivitamin users to 40 percent of the total number of participants, as these individuals typically have milder homocysteine reduction in response to high-dose supplements than do non-vitamin users.

Key data, based on lab tests and cognitive and behavioral assessments done at baseline, and every three months thereafter, were remarkably clear-cut. By six months, the mean baseline homocysteine level among treated subjects had dropped about 30 percent relative to the placebo group, and held steady for the remainder of the 18-month study. However, these changes brought no cognitive gain, as mean ADAS-Cog scores for the treatment and placebo groups were statistically indistinguishable across all seven time points. The two groups also did not differ on any of the study’s secondary outcome measures (CDR sum of boxes, Neuropsychiatric Inventory, ADCS-ADL, probability of surviving to any of five clinically relevant end points). The only noteworthy difference between treatment and placebo arms was the unfortunate overrepresentation of depression-related adverse events among participants who got the supplement (28 percent, versus 18 percent in placebo). However, the treatment and placebo groups had the same 18-month change in depression subscores of the Neuropsychiatric Inventory, and the percentage of subjects starting antidepressants during the trial was similar in the two groups (21 percent in placebo, 26 percent in treatment).

A number of prior randomized trials looking at cognitive effects of homocysteine lowering by B vitamin supplementation have produced similarly disappointing results (Balk et al., 2007). But the outcome of the recent ADCS study fell with a greater thud because this was widely believed to be the most comprehensive analysis of long-term B vitamin treatment for dementia to date.

Still, some see a silver lining in what the ADCS trial did not address. “While I think the results are definitive for mild to moderate AD, I don't think they say there's no hope for this approach earlier in the disease,” Aisen told ARF. “It remains unknown whether B vitamins can play a therapeutic role in mild cognitive impairment (MCI) or presymptomatic AD, or simply in risk reduction.”

Inna Kruman of Texas Tech University Health Sciences Center in Lubbock told ARF she believes the vitamin B supplementation could work as a preventive measure but not once neurodegeneration is ongoing. She noted that one of very few trials to show cognitive benefit from vitamin B supplements tested a three-year folate regimen in 50-70-year-old adults with raised homocysteine levels but no dementia (Durga et al., 2007).

Sudha Seshradi of Boston University, as well as the authors, pointed out that vitamin B supplementation could be useful for people with high baseline plasma homocysteine levels—for example, in countries where grain products are not routinely supplemented with folate. In her 2002 prospective study (Seshadri et al., 2002) linking elevated homocysteine and AD, she saw doubled risk of dementia or AD in people with homocysteine levels around 13 or 14 μ/dl. In the current study, no treatment effect was seen even in patients with the highest homocysteine levels, but mean levels at baseline were just 9 μg/dl.

In other vitamin-related news, researchers led by Vin Tangpricha at Emory University School of Medicine in Atlanta, Georgia, report a greater prevalence of vitamin D deficiency among patients with Parkinson disease (55 percent) compared with healthy subjects (36 percent) and those with AD (41 percent). Writing in this month’s Archives of Neurology, first author Marian Evatt and colleagues measured vitamin D concentrations in plasma samples from a cohort of mostly white adults (100 PD, 97 AD, 99 control) in a research registry at the university. The authors say the data support a previously suggested link between vitamin D insufficiency and Parkinson disease, and should stimulate further study into how shortage of this vitamin might contribute to pathogenesis.—Esther Landhuis

Comments

Our findings in B6-deficient diet are based on the controversial situation of homocysteine risk factor for Alzheimer disease. The New England Journal of Medicine reported that administration of vitamin B6, folic acid and vitamin B12 to older persons did not prevent their cognitive decline, and the author expressed doubt of the homocysteine risk factor. But our B6-deficient condition suggested that homocysteic acid is indeed a real risk factor. B6-deficient food induced a high level of homocysteine, homocysteic sulfonic acid, and homocysteic acid. Then B6-deficient condition is a good means for inducing the homocysteine risk factor in 3xTg-AD mice. Our anti-HA antibody or vaccine treatment did give a strong answer that homocysteic acid is a real risk factor of homocysteine risk and consequently is a real pathogenic factor.

Recently many papers reported that homocysteine induced Aβ40/42, and these phenomena may be related to the homocysteine risk factor for Alzheimer disease. But recent unsatisfactory results of clinical amyloid treatments raised doubt about the amyloid pathogen of Alzheimer disease.

Our findings in B6-deficient conditions give a strong reply that amyloid beta is not related to the homocysteine risk factor and that homocysteic acid is a real homocysteine risk factor.

The manuscript with our findings on anti-HA antibody treatment in 3xTg-AD mice is available at Nature Precedings